Outline

Ductal adenocarcinoma of the pancreas show a specific pattern of genetic lesions and are characterized by genomic instability, invasiveness and rapid progression. Their profound resistance to chemotherapy is due to changes in signalling pathways controlling proliferation and cell death. Members of the CK1 kinase family, especially CK1 alpha, deltaand epsilon, are playing important regulatory roles in these pathways and have been shown to impede receptor mediated apoptosis on different levels. In the present study we show that CK1 delta and epsilon are constitutively expressed at higher protein levels in pancreatic tumor cells than CK1 alpha and that the well characterized CK1 delta/epsilon specific inhibitor IC261 (3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one) abolishes the growth of all analyzed pancreatic tumor cell lines. IC261 treatment led preferently to an accumulation of cells in G2/M 24h after IC261 treatment. Interestingly, incubation of Panc89 cells with IC261 lead to a decreased expression of anti-apoptotic proteins like c-IAP1, c-IAP2, XIAP and BCL-xL and strongly sensitised these cells to CD95-mediated cell death. Similar results were obtained using another CK1 inhibitor CKI-7. Taken together, our results show that targeting CK1 isoforms, especially CK1 delta and epsilon, could provide a powerful strategy for the treatment of pancreatic tumors.